The synthetic progestin, gestodene, affects functional biomarkers in neonatal rat osteoblasts through an estrogen receptor-related mechanism of action.

Background: Clinical studies have shown that gestodene (GDN), a potent third-generation synthetic progestin, affects bone resorption. However, its mode of action in bone cells is not fully understood. The aim of this study was to establish whether GDN affects bone directly or through its bioconversion to other metabolites with different biological activities.

Methods: In this study, we investigated the effects of GDN and its A-ring reduced metabolites on proliferation, differentiation, and mineralization of calvarial osteoblasts isolated from neonatal rat and their capacity to displace [H]-E at ER binding sites.

Results: In contrast to progesterone, gestodene did exert significant effects on osteoblast activities. The most striking finding was the observation that the A-ring reduced derivatives 3β,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN, though to a lesser extent, had greater stimulatory effects on the osteoblast activity than those observed with GDN. The effects on osteoblast proliferation and differentiation induced by GDN-reduced derivatives were abolished by the antiestrogen ICI 182780, consistent with their binding affinities for the estrogen receptor. In addition, the presence of a 5α-reductase inhibitor or inhibitors of aldo-keto hydroxysteroid dehydrogenases abolished the GDN-induced enhancement of osteoblast differentiation. These results indicated that GDN is metabolized to the A-ring reduced metabolites with estrogen-like activities and through this mechanism, GDN may affect the osteoblast activity.

Conclusion: Together, the data suggest that synthetic progestins derived from 19-nortestosterone such as GDN, have beneficial effects on bone due to their biotransformation into metabolites with intrinsic estrogenic activity.